Stem cell reprogramming clues revealed

During one of the most linkurl:memorable;http://www.the-scientist.com/blog/display/23254/ conference sessions I attended, a researcher from Japan wowed an entire Keystone meeting on stem cells by announcing he had found a way to reprogram adult stem cells into embryonic stem cells using only a few factors. What those factors were, however, Shinya Yamanaka from Kyoto University wouldn?t say -- even after numerous probing questions from the audience.
Now, Yamanaka is revealing his secrets in the

By Alison McCook | August 11, 2006

During one of the most linkurl:memorable;http://www.the-scientist.com/blog/display/23254/ conference sessions I attended, a researcher from Japan wowed an entire Keystone meeting on stem cells by announcing he had found a way to reprogram adult stem cells into embryonic stem cells using only a few factors. What those factors were, however, Shinya Yamanaka from Kyoto University wouldn?t say -- even after numerous probing questions from the audience.
Now, Yamanaka is revealing his secrets in the linkurl:latest issue;http://www.cell.com/content/article/abstract?uid=PIIS0092867406009767 of Cell. He and his colleague describe translating adult fibroblasts into pluripotent stem cells using only four factors -- Oct 3/ 4, Sox2, c-Myc, and Klf4. Surprisingly, the researchers didn?t need to use Nanog, a key ingredient in maintaining pluripotency.
I hope my fellow conference attendees feel the findings are worth the wait. Personally, I?m skeptical of the claim that reprogramming -- a long sought-after mechanism that would sidestep ethical issues surrounding embryonic cells -- requires such simple steps. Only further experiments will reveal whether four factors are all you need to dive into reprogramming with full gusto.

Comments

One must keep in mind that the Yamanaka induction of pluripotent stem cells is from MOUSE embryonic or adult fibroblasts, not HUMAN fibroblasts. It offers great hope as a proof-of-concept model, but it has not been performed using human tissue...yet. Somatic Cell Nuclear Transfer has been successfully performed using numerous animal tissue, but never HUMAN. The other concern with the Yamanaka technique is the use of retrovirus vectors to introduce the transciption factors. This would make it difficult to obtain GMP standards for human use. Both SCNT and the Yamanaka technique should be explored using human tissue as a source for obtaining patient-specific human embryonic stem cells.

I wish to express my strong doubt towards the induction claim for producing pluripotent stem cells from normal skin cells. Immediately after the publication of the Nature paper by Yamanaka?s group (Okita et al., 2007) I sent Yamanaka a Communications Arising manuscript expressing my doubt on the inductive nature of the iPS cells (Liu, 2007d) and asked him to respond. In his initial but formal response (made on behalf of all other authors) (Liu, 2007c) he admitted that ?the origin of iPS cells may be tissue stem or progenitor cells co-existing in fibroblast cultures?. As to the experiments that I proposed to him for reaching a conclusive answer on whether the iPS cells are induced from normal (differentiated) skin cells or simply the detected and expanded pre-existing stem cells, he stated that ?I agree that the experiments you[r] proposed are important.?\nUnfortunately these ?important? experiments have been put aside and Yamanaka still spin heavily on his shaky induction claim. The inclusion of a sentence that ?the origin of iPS cells may be undifferentiated stem or progenitor cells? in the discussion section of their new Cell paper (Takahashi et al., 2007) is apparently an attempt to deflect criticisms rather than a sincere expression of their doubt. As a matter of fact, in their later response to me as guided by Nature, Yamanaka essentially denied the possibility of the pre-existing stem cells as the origin of the iPS cells (Liu, 2007c). \nIn the eyes of cloning/stem cell experts, Yamanaka?s procedure for iPS cells represents a ?Dolly?-level achievement (Wilmut and Taylor, 2007). This new study on producing human iPS cells represents another ?milestone? for cloning (Zaehres and Scholer, 2007) and even the Wright brothers? airplane for therapeutic cloning (Harris, 2007). However, I wish to say that the induction claim for pluripotent stem cells suffers from some fundamental deficiencies (Liu, 2007a; Liu, 2007b; Liu, 2007c; Liu, 2007e). Thus, I sincerely wish that Yamanaka will take a pause in further spinning on this unsubstantiated induction claim and do the important control experiments already suggested to him.\n\nShi V. Liu\nEagle Institute of Molecular Medicine\nApex, NC 27502, USA\nSVL@logibio.com\n\nReferences.\n\nHarris, S. D. (2007). Stem cell breakthrough. MercuryNewscom http://origin.mercurynews.com/businessupdate/ci_7516801?nclick_check=1, 2007-2011-2020.\nLiu, S. V. (2007a). Are iPS cells really indistinguishable from ES cells? Logical Biology 7, 66-68.\nLiu, S. V. (2007b). Can the iPS airplane really fly high in the therapeutic sky? Logical Biology 7, 84-96.\nLiu, S. V. (2007c). Further comments on the nature of iPS cells. Logical Biology 7, 69-72.\nLiu, S. V. (2007d). iPS cells: stem cells induced from terminally differentiated cells or just pre-existing stem cells being detected? Logical Biology 7, 63-65.\nLiu, S. V. (2007e). Nuclear transplatation-derived embryonic stem cells are distinct from those emerging fom fertilization. Submitted.\nOkita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317.\nTakahashi, K., Tanabe, K., Ohnuki, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell doi:10.1016/j.cell.2007.11.019.\nWilmut, I., and Taylor, J. (2007). Primates join the club. Nature.\nZaehres, H., and Scholer, H. R. (2007). Induction of pluripotency: From mouse to human. Cell 131, 834-835.\n\n\n1. Further readings of collected publications on the related topics:\nStem cells (http://im1.biz/StemCell.htm or http://im1.biz/StemCell.pdf)\nCloning (http://im1.biz/Cloning.htm or http://im1.biz/Cloning.pdf)\nAging (http://im1.biz/Aging.htm or http://im1.biz/Aging.pdf)\n\n2. List of my recent Comments posted in Nature News on cloning and iPS cells:\nSafer way to make human stem-like cells revealed\nhttp://www.nature.com/news/2007/071205/full/450775a.html\nStem cells treat anaemia in mice\nhttp://www.nature.com/news/2007/071206/full/news.2007.347.html\n\n

I wish to express my strong doubt towards the induction claim for producing pluripotent stem cells from normal skin cells. Immediately after the publication of the Nature paper by Yamanaka?s group (Okita et al., 2007) I sent Yamanaka a Communications Arising manuscript expressing my doubt on the inductive nature of the iPS cells (Liu, 2007d) and asked him to respond. In his initial but formal response (made on behalf of all other authors) (Liu, 2007c) he admitted that ?the origin of iPS cells may be tissue stem or progenitor cells co-existing in fibroblast cultures?. As to the experiments that I proposed to him for reaching a conclusive answer on whether the iPS cells are induced from normal (differentiated) skin cells or simply the detected and expanded pre-existing stem cells, he stated that ?I agree that the experiments you[r] proposed are important.?\nUnfortunately these ?important? experiments have been put aside and Yamanaka still spin heavily on his shaky induction claim. The inclusion of a sentence that ?the origin of iPS cells may be undifferentiated stem or progenitor cells? in the discussion section of their new Cell paper (Takahashi et al., 2007) is apparently an attempt to deflect criticisms rather than a sincere expression of their doubt. As a matter of fact, in their later response to me as guided by Nature, Yamanaka essentially denied the possibility of the pre-existing stem cells as the origin of the iPS cells (Liu, 2007c). \nIn the eyes of cloning/stem cell experts, Yamanaka?s procedure for iPS cells represents a ?Dolly?-level achievement (Wilmut and Taylor, 2007). This new study on producing human iPS cells represents another ?milestone? for cloning (Zaehres and Scholer, 2007) and even the Wright brothers? airplane for therapeutic cloning (Harris, 2007). However, I wish to say that the induction claim for pluripotent stem cells suffers from some fundamental deficiencies (Liu, 2007a; Liu, 2007b; Liu, 2007c; Liu, 2007e). Thus, I sincerely wish that Yamanaka will take a pause in further spinning on this unsubstantiated induction claim and do the important control experiments already suggested to him.\n\nShi V. Liu\nEagle Institute of Molecular Medicine\nApex, NC 27502, USA\nSVL@logibio.com\n\nReferences.\n\nHarris, S. D. (2007). Stem cell breakthrough. MercuryNewscom http://origin.mercurynews.com/businessupdate/ci_7516801?nclick_check=1, 2007-2011-2020.\nLiu, S. V. (2007a). Are iPS cells really indistinguishable from ES cells? Logical Biology 7, 66-68.\nLiu, S. V. (2007b). Can the iPS airplane really fly high in the therapeutic sky? Logical Biology 7, 84-96.\nLiu, S. V. (2007c). Further comments on the nature of iPS cells. Logical Biology 7, 69-72.\nLiu, S. V. (2007d). iPS cells: stem cells induced from terminally differentiated cells or just pre-existing stem cells being detected? Logical Biology 7, 63-65.\nLiu, S. V. (2007e). Nuclear transplatation-derived embryonic stem cells are distinct from those emerging fom fertilization. Submitted.\nOkita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317.\nTakahashi, K., Tanabe, K., Ohnuki, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell doi:10.1016/j.cell.2007.11.019.\nWilmut, I., and Taylor, J. (2007). Primates join the club. Nature.\nZaehres, H., and Scholer, H. R. (2007). Induction of pluripotency: From mouse to human. Cell 131, 834-835.\n\n\nFurther readings of collected publications on the related topics:\nStem cells (http://im1.biz/StemCell.htm or http://im1.biz/StemCell.pdf)\nCloning (http://im1.biz/Cloning.htm or http://im1.biz/Cloning.pdf)\nAging (http://im1.biz/Aging.htm or http://im1.biz/Aging.pdf)\n\n

A method for identifying/amplifying pre-exiting adult stem cells has been characterized as a method for inducing/generating embryonic-like stem cells. The so-called 'induced pluripotent stem (iPS) cells' were even equated with Wright brothers' first airplanes. While these safe therapy-unproven stem cell 'airplanes' are shown up everywhere in the western publishing 'radars' some therapy-led discoveries of regenerative stem cell 'airplanes' made in China are still undetected or, even worse, detected but intentionally ignored by the western 'radars'. \n\nFull-length paper can be read free at:\nhttp://im1.biz/albums/userpics/10001/TW2007V2N2A25_Radar.htm\nhttp://im1.biz/albums/userpics/10001/TW2007V2N2A25_Radar.pdf\n\nMore papers on iPS cells can be found at:\n\nhttp://im1.biz/cloning.htm\nhttp://im1.biz/cloning.pdf\n

A paper entitled was rejected by Nature due to space limitation. It is now published in Logical Biology. It can be found free in two formats:\n//PDF (http://im1.biz/albums/userpics/10001/LB2008V8N1A3_Yamanaka.pdf)\n//HTM (http://im1.biz/albums/userpics/10001/LB2008V8N1A3_Yamanaka.htm)\n//\nIn addition, more articles on iPS cells and cloning can be found at http://im1.biz/Cloning.htm\n\n----------------\nShi V. Liu (SVL@logibio.com)\n